Cylinder-piston unit suitable for storing injection solutions for a needle-free injector and method for the bubble-free automatic or manual filling of the cylinder-piston unit, also under atmospheric pressure

ABSTRACT

A pressure-stable cylinder/piston unit which blocks water vapor and oxygen and is designed for a needle-free injector, with a chamber arranged in a cylinder, which blocks water vapor and oxygen, and designed for long-term and sterile storage of an injection solution, an end wall with at least one nozzle bore or one outlet element, a pressure-stable outer cylinder, and a pressure-stable piston arranged movably in the chamber and blocking water vapor and oxygen. Methods for bubble-free, automatic or manual filling of the cylinder/piston unit, also at atmospheric pressure are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATION

This is a divisional of and claims the benefit of U.S. patentapplication Ser. No. 13/304,469 filed Nov. 25, 2011, which applicationis incorporated herein by reference in its entirety. The said U.S.patent application Ser. No. 13/304,469 is a continuation-in-partapplication of pending international application PCT/EP2010/002975 filedMay 14, 2010 and claiming the priority of German Application No. 10 2009023 334.2 filed May 29, 2009

BACKGROUND OF THE INVENTION

The invention relates to a pressure-stable cylinder/piston unit whichblocks water vapor and oxygen and is designed for a needle-freeinjector, with a chamber arranged in a cylinder, which blocks watervapor and oxygen, and designed for long-term and sterile storage of aninjection solution, an end wall with at least one nozzle bore or oneoutlet element, a pressure-stable outer cylinder, and a pressure-stablepiston arranged movably in the chamber and blocking water vapor andoxygen.

The invention further relates to methods for bubble-free, automatic ormanual filling of the cylinder/piston unit, also at atmosphericpressure.

Cylinder/piston units are used in injectors and disposable injectorswhich are known, for example, from US 2008/0146997 A1, DE 10 2007 004211 A1 or DE 10 2007 008 369 A1. None of these cylinder/piston units issuitable for long-term storage of injection solutions, e.g. over a year,since they are unable to block water vapor and oxygen.

Injection solution is understood as liquid medicaments. The specialistterms used will now be explained in detail. The term medicament is knownto the person skilled in the art. This is understood as substances ormixtures of substances for human or veterinary medicine. They consist ofthe pharmaceutical active substance or substances, and of furtherstandard components that make this active substance usablepharmaceutically, in particular water.

DE 10 2005 054 600 A1 discloses a cylinder/piston unit having a cylinderand a piston which is guided therein, wherein the cylinder and thepiston enclose a chamber that can be filled at least for a time with anactive substance, and the cylinder has at least one outlet element atits front end. The cross section of the chamber or the cross section ofthe cylinder inner wall increases at least in regions from the front tothe back. At least in the front area directed toward the outlet element,the piston has a front elastic skirt, the front outer edge of whichdefines, when the piston is unloaded, a cross-sectional surface which isgreater than a surface that is defined by a contour line and that liesin the area of transition from the skirt to the section of the pistoncarrying the skirt.

DE 10 2006 040 888 B3 discloses a closure system for containers used forstoring or administering substances in the form of liquids, pastes orpowders, said system consisting of a cap, provided with a through-hole,and of a closure element. The cap holds the closure element with a forcefit and/or form fit on the container by means of a catch element presenton the container in the area of the opening that is to be closed. Theend face which surrounds the opening of the container, and on which theclosure element bears, has a depression. The closure element is avirus-proof, bacteria-proof and spore-proof film that lies on the endface and, at least in some areas, over the depression. When the cap isfitted in place, an elastomer ring or adhesive ring is arranged betweenthe closure element and the depression and fills the depression.

DE 10 2006 045 959 B3 discloses a cylinder/piston unit including acylinder and a piston guided in the cylinder and sealed off in a sterilemanner by a rubber seal, wherein the cylinder and the piston enclose achamber that can be filled at least for a time with active substance,and the cylinder has at least one outlet element at its front end. Thepiston, resting in a rear position, is sealed off relative to thecylinder in a sterile manner by a static rear sealing element, whereinboth sealing elements each respectively bear on the wall of the cylinderand on the wall of the piston in a sealing position. Arranged spatiallybehind each static sealing element, there is a parking area forreceiving the respective sealing element. When the piston is actuated,the individual static sealing elements are transferred from theirrespective sealing position to a parked position located in the parkingarea, wherein each sealing element in the parked position touches eitheronly the cylinder wall or only the piston wall. Arranged between the twostatic sealing elements, there is at least one dynamic sealing elementon the piston side, which dynamic sealing element bears on the innerwall of the cylinder at least when the piston is actuated.

In the described cylinder/piston unit, a closure element is inserted asa piston into the prefilled medicament chamber in the vacuum applicationprocess. Under vacuum, the closure element is placed on the liquid levelof the medicament that has been introduced into the chamber. This methodand the devices required for it are expensive and complicated,

Proceeding from this prior art, the objects of the invention are

object 1—to define a pressure-stable cylinder/piston unit and methodtherefor which blocks water vapor and oxygen and is designed forlong-term sterile storage of an injection solution, and methods forbubble-free filling of the cylinder/piston unit, also in a tray, wherethe piston can be introduced more easily and at atmospheric pressureinto the cylinder, in order to reduce the costs for the device and themethod. At the same time, however, it is also intended to allow manualfilling, for example of small batch numbers, such that, for example, nofilling machine is needed for the clinical specimens;

object 2—to safely avoid underdosing (partial administration) or nodosing (rebound of the injection stream) (no wet-shot);

object 3—to avoid the return flow of injection solution from theinjection channel;

object 4—to avoid the bubble formation that is possible starting fromadministration volumes of more than 150 microliters.

SUMMARY OF THE INVENTION

These objects are achieved in the first instance by the method of claim1. Accordingly, the pressure-stable cylinder/piston unit which blockswater vapor and oxygen is characterized in that the chamber is designedwith a first chamber and a second, concentric chamber, wherein the crosssection of the first chamber is greater than the cross section of thesecond chamber, and each nozzle bore or each outlet element is closed ina sterile manner by a membrane that blocks water vapor and oxygen andthat opens at an overpressure. By means of such a configuration, acontact surface or annular surface is created on which the piston comesto bear, e.g. with a U-profile seal that is squeezed upon insertion intothe first chamber and allows air to escape,

Object 2 is achieved by the design of the nozzle outlet.

The nozzle outlet ends in a raised (protruding) truncated cone, suchthat the skin is pressed on during injection, and the injection solutionpenetrates the skin at relatively low pressure. This is helped by theunderlying subcutaneous fatty tissue, which constitutes looser tissuecompared to the cutis. Since the stream of injection solution does notimpact the skin in free flight, it also cannot partially or completelyrebound off the surface. It is quantitatively administered, and awet-shot is avoided.

Object 3 is achieved by plug-like closure of the skin. Since the nozzleoutlet is closed by the piston, in particular the inner piston body, theraised truncated cone forms a plug at the injection site. If it is leftin place for a few seconds on the skin until the pressure in the skinhas dropped as a result of the distribution of the injection solution,no return flow can occur.

Object 4 is achieved by a multi-nozzle model, e.g. a four-nozzle model,such that up to 0.6 milliliter can be administered free of bubbles.Experience shows that needle-free subcutaneous injections with volumesof greater than 150 microliters cause subcutaneous bubble formation. Theversion presented here by way of example has four outlet elements and istherefore able to administer injection volumes of up to 0.6 milliliter.

By a preferred embodiment of the piston in an inner piston body withflange and an outer piston ring that blocks water vapor and oxygen andprovides a sterile seal, for example in the form of a U-profile or of asterile seal with another shape that overlaps the flange blocking watervapor and oxygen, different materials may be considered for the piston.For closing the chamber, or the second chamber filled with injectionsolution, and for the subsequent possible storage for up to one year,the outer piston ring is made of a rubber approved for medicine, e.g.West 4590. Upon insertion into the first chamber, the outer piston ringis pressed such that a channel or a flow edge arises through which thedisplaced air can escape from the chamber without pressure. A gascushion, located entirely in the second chamber, remains between thepiston and the injection solution. In a further step, this gas cushionis removed from the second chamber by means of the chamber beinginverted (air to nozzle) and the inner piston body of the piston beingpressed into the second chamber. The flange and the external diameter ofthe inner piston body are adapted to the internal diameter of the secondchamber. When air is removed completely from the second chamber, theinner piston body is located entirely within the second chamber. Theguiding of the inner piston body is at all times ensured by aconfiguration of this kind.

During the subsequent injection of the injection solution by means of adrive unit, the cylinder/piston unit is received by, for example, springhooks of the drive unit. An alternative embodiment involves screwing thecylinder/piston unit into the drive unit, providing it with a flange orbayonet closure.

For the injection, the engaged closure cap with the membrane fitted overit is removed, and, with the aid of the piston rod actuated by the driveunit (for example by a pretensioned spring), the inner piston body withflange is pushed in as far as the end of the second chamber and soquickly that the speed of the stream of liquid emerging from thenozzle(s) is sufficient for penetration of the skin.

In a preferred embodiment, the inner piston body is designed with atleast one sealing lip, wherein the leak tightness between the innerpiston body and the wall of the second chamber increases as the pressurerises.

The abovementioned object is also achieved by a method using thecylinder/piston unit just described above. The method comprises at leastthe following steps:

filling a second chamber with an injection solution, wherein the volumeof the injection solution is smaller than the volume of the secondchamber;

inserting a piston, designed for example with a squeezed U-profile ringseal, into a first chamber until it bears on an annular surface in orderto close the second chamber, wherein a gas cushion remains in the secondchamber;

rotating the piston/cylinder unit through ca. 180° about the horizontalaxis and waiting until the gas cushion in the second chamber has risenfully upward to at least one nozzle bore or one outlet element;

moving an inner piston body with flange, by means of a piston rod, outof the outer U-profile piston ring into the second chamber, wherein thegas cushion is forced through the nozzle bore(s) or outlet element(s)from the second chamber, and, upon emergence of the gas cushion, aclosure cap with membrane, or a separate membrane acting as overpressurevalve, lifts away from the nozzle bore(s) or outlet element(s) andannular pressure contours A, B and C, and, after the emergence of thegas cushion, again closes the nozzle bore(s) or outlet element(s) on theannular pressure contours A, B and C in a sterile manner (overpressurevalve function),

The method ensures that the cylinder/piston unit is completely filledand that, without further measures, it can be separately stored or canbe used in a drive unit. Providing the closure cap with a membraneensures at all times that the injection solution remains sealed in asterile manner at three places on the annular pressure contours A, B andC.

For manual filling, e.g. for clinical tests, the piston is positionedabout 2-3 mm in front of the annular surface. With the nozzle pointingupward, the injection solution is injected through the outer piston ringinto the chamber. By advancing the piston as far as the annular surface,and by further advancing the inner piston body with flange, the air isforced through the overpressure valve formed by the membrane.

In a development of the method, it is proposed that the completeemergence of the gas cushion is detected. For this purpose, for example,the nozzle bore(s) or outlet element(s) is/are monitored by a lightbarrier for the emergence of the injection liquid. As soon as a changeis detected, the insertion of the inner piston body is directly stopped.

Since the air requires a much lower advancing force of the piston thandoes the injection solution, the switching-off of the piston advance canalso be thereby controlled.

With the present-day accuracy of liquid metering and the precision ofinjection-molded chambers, it is also possible to compute the advancemovement of the piston rod. In the case of small batch numbers, themovement of the air bubble is monitored by sight.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and details of the invention will become clear from anillustrative embodiment depicted in schematic drawings, in which:

FIG. 1 shows a sectional side view of a cylinder of a cylinder/pistonunit, with an engaged closure cap with membrane;

FIG. 2 shows the cylinder from FIG. 1 sitting, for example, in the trayin the filling machine, after sterile filling of the injection liquidonly into the second chamber;

FIG. 3 shows the cylinder from FIG. 2 after the piston, consisting of aninner piston body with flange and of an outer piston ring, has beeninserted in a pressure-free, sterile manner into the first chamber,flush onto the annular surface not wet with injection solution, and aremaining air pocket;

FIG. 4 shows a sectional side view of the cylinder/piston unit rotatedthrough 180° about the horizontal axis, such that the air pocketmigrates to the outlet nozzle;

FIG. 5 shows a sectional side view of the cylinder/piston unit accordingto FIG. 4, wherein the injection solution completely fills the secondchamber; additionally alternative membrane fitting, spring hook andtrigger;

FIG. 6 shows a cylinder/piston unit after removal of the closure capwith membrane and actuated injection; trigger path;

FIG. 7 shows manual filling of the single-nozzle cylinder/piston unitusing a syringe;

FIG. 8 shows manual filling of the multi-nozzle cylinder/piston unitusing a syringe;

FIG. 9 shows a bottom view of the end wall of a cylinder with onenozzle; and,

FIG. 10 shows a bottom view of the end wall of a cylinder with fournozzles.

In all of the figures, the same technical elements are designated by thesame reference signs.

DETAILED DESCRIPTION OF THE PARTICULAR EMBODIMENTS

FIG. 1 is a sectional side view of a cylinder/piston unit 1. A chamber 3of a cylinder 2 that blocks water vapor and oxygen is formed by a firstchamber 8 and by a second, concentric chamber 9, wherein the crosssection of the first chamber 8 is greater than the cross section of thesecond chamber 9. A pressure-stable outer cylinder 13 substantiallysurrounds in contacting relationship the cylinder 2 proximate the secondchamber 9. On the side directed away from the first chamber 8, proximatethe second chamber 9 the outer cylinder 13 on the outside 12 thereofincludes an end wall 5, which has at least one nozzle bore or at leastone outlet element 6 passing therethrough. Each nozzle bore or eachoutlet element 6 ends on the outside 12 of the pressure-stable outercylinder 13 in a raised truncated cone 29 proximate end wall 5 and has,on an inside 14 of the chamber 9, an outflow funnel 15. On the outside12 of the pressure-stable outer cylinder 13, a membrane 26, for examplemade of rubber or transparent silicone, that blocks water vapor andoxygen, is stretched over the outlet element(s) 6 and preferablysupported by the closure cap 10. Alternatively, a membrane 27 can besecured on the outer cylinder 13 as a sterile closure and overpressurevalve.

Between the first chamber 8 and the second chamber 9, a transition areais formed, preferably as an interior annular surface 16 of cylinder 2. Afirst embodiment of the transition area provides radii (not shown) atthe transition from the cylindrical wall of the first chamber 8 to theannular surface 16 and from the annular surface 16 to the cylindricalwall of the second chamber 9. A second embodiment of this area providesbevels (not shown). Other embodiments, including combinations of, forexample, radii and bevels, negative or positive camber, and concave orconvex, can be considered. The embodiments help, on the one hand, whenfilling the injection solution 4 (see FIG. 2) and, on the other hand,when producing the cylinder 2, which is produced for example by aninjection molding technique or from glass. By virtue of the embodimentsdescribed, above, the flow behavior of the particular material blockingwater vapor and oxygen is supported, in order to achieve a cylinder 2with the predetermined properties such as perpendicularity,concentricity, wall thickness, etc.

Using known devices, the injection solution 4 is introduced into thesecond chamber 9 in such a way that the second chamber 9 is notcompletely filled. The filling is carried out under atmosphericpressure. The filling of each cylinder 2 is carried out separately or ingroups, wherein, for example, twenty cylinders in a matrix of four×fivein a tray are filled simultaneously.

A piston 7 as a multi-part closure element is then pushed into the firstchamber 8 at atmospheric pressure, as is shown in FIG. 3. The closureelement, composed of an outer piston ring 17 and of an inner piston body18 with a flange 22 that blocks water vapor and oxygen, is pushed intothe first chamber 8 until contact is made with the annular surface 16.The outer piston ring 17 is squeezed laterally by the setting head ofthe filling machine, such that when it is inserted into the firstchamber 8 it does not exert any pressure on the injection solution 4located in the second chamber 9. Methods and devices for pressure-freeinsertion of a stopper or of a closure piece are known. For example, theouter piston ring 17 is deformed such that the gas, in the present caseair, located between closure element and injection solution 4, is notcompressed and instead can escape. After removal of the setting head,the U-profile sealing ring closes in a sterile manner, blocking watervapor and oxygen,

After placement of the piston 7, composed of the outer piston ring 17and of the inner piston body 18 with flange 22, which can also bedesigned separately from a piston rod 21, a gas bubble/air pocket 19 andthe injection solution 4 are located in the second chamber 9. To removethe gas bubble/air pocket 19, the cylinder/piston unit 1 is rotatedthrough ca. 180° about the horizontal axis. The end wall 5, with theattached closure cap 10 and the membrane 26, now points upward, as isshown in FIG. 4. The gas bubble/air pocket 19 located in the secondchamber 9 rises to the top and is located between the upper edge 20 ofthe injection solution 4 and the nozzle bore(s) or outlet opening(s) 6.When the gas bubble 19 is entirely located over the upper edge 20 of theinjection solution 4 (the time needed for this depends on, among otherthings, the viscosity of the injection solution 4, the surroundingtemperature etc., and is taken into consideration in the subsequentmethod steps), the inner piston body 18 of the closure element is movedupward by means of the piston rod 21 and the flange 22. The outer pistonring 17 remains fixed in position, bearing on the annular surface 16.The inner piston body 18 with flange 22 is pushed into the secondchamber 9 until the gas bubble/air pocket 19 has escaped completelythrough the nozzle bore(s) or outlet opening(s) 6 from the secondchamber 9, as is shown in FIG. 5. For this purpose, a membrane 26 of theclosure cap 10 lifts away from the annular pressure contours A, B and Cwhen there is an overpressure in the second chamber 9. The sterile airthus passes the sterile membrane 26 and escapes through the gap betweenthe cylinder and the transparent closure cap 10. The complete expulsionof the gas bubble/air pocket 19 from the second chamber 9 is detected bymeasurement methods and measurement devices known per se (lightbarrier), by means of the injection solution 4 being detected in thenozzle bore(s) or outlet opening(s) 6. Another variant involves theinner piston body 18 being pushed into the second chamber 9 as far as apredetermined position. In a further variant, the advance movement isswitched off under electronic control when the advancing force of thepiston abruptly increases after the air escapes.

As is shown in FIG. 5, the piston rod 21 is designed with a flange 22,although the flange 22 can also be designed separately from the pistonrod 21. In the case of a fully filled chamber 9, the edge of the outerpiston ring 17 is flush with the flange 22 of the piston rod 21. Thediameter of the pretensioned sealing lip 31 of the inner piston body 18is chosen such that, with rising pressure, it can engage sealingly inthe second chamber 9 upon ejection of the injection solution 4 from saidsecond chamber 9. The pressure-stable outer cylinder 13 is designed, onthe jacket surface 11, with retainer elements 23, such as a slit,thread, flange or bayonet. The drive unit of the disposable injector isdesigned to complement the shape of the retainer elements 23. In orderto eject the injection solution, the inner piston body 18 with flange 22is moved by the piston rod 21 in the direction of the end wall 5. Thisis done, for example, by a pretensioned spring, as is described in moredetail in the abovementioned documents concerning disposable injectors.Cylinder 2 and flange 22 must block water vapor and oxygen during atwelve-month period of storage of the cylinder/piston unit filled withinjection solution 4.

Besides glass, suitable materials for the cylinder 2 and the flange 22are also transparent, amorphous thermoplastics, e.g. a copolymer basedon cycloolefins and ethylenes or α-olefins (COC or COP).

The outer cylinder 13 has to be able to withstand for a short time (afew milliseconds) a pressure of up to 350 bar and must therefore be madeof a pressure-stable material, for example polycarbonate (PC) orpolyurethane (PU).

The material used for the inner piston body 18 is atetrafluoroethylene/hexafluoropropylene copolymer (FEP). This hasself-lubricating properties in conjunction with the aforementionedmaterials of the cylinder 2 or inner part, such that no separatelubricants are needed between the inner piston body 18 and the cylinder2. Alternative materials that can be chosen include perfluoroalkoxycopolymer (PFA), tetrafluoroethylene (E TFE) or polyvinylidene fluoride(PVDF).

The material used for the outer piston ring 17 is a rubber, such asHelveot FM 257, Heivoet FM 460, Stelmi 6422, Stelmi 6720 or West 4590.The membrane 26 can be made of the same materials that close in asterile manner and block water vapor and oxygen.

FIG. 6 shows a cylinder/piston unit 1 after removal of the closure capwith membrane 26 and actuated injection. An alternative configuration ofthe outside of the end wall 12 is shown on the left-hand side. By virtueof the raised configuration of the cone 29 surrounding the nozzle 6, theskin is pressed on and therefore more easily traversed by the injectionstream. The injection solution 4 then spreads out in the subcutaneousfatty tissue, which is looser compared to the cutis. Quantitativeadministration is ensured in this way. Since the nozzle 6 is closed bythe inner piston body 18 lying at the bottom, the truncated cone 29 actsas a lid on the skin channel, such that a return flow of the injectionsolution is avoided. After a few seconds, the pressurized injectionsolution has become distributed in the looser subcutaneous fatty tissue,and the injection channel in the skin has contracted. The injector canthen be removed from the injection site.

FIG. 7 shows sterile filling by hand, e.g. for a clinical test, withouta complicated filling machine. For this purpose, at the time ofmanufacture, the piston unit 7, consisting of inner piston body 18 withflange 22 and of outer U-profile piston ring 17 closed by a profile ring30, is placed into the first chamber 8 only 2-3 mm in front of theannular surface 16. This cylinder/piston unit 1 is thengamma-sterilized. The sterile profile ring 30 can then be removed in thehospital. The needle of a syringe filled with injection solution canthen be inserted into the hollow space of the U-profile 17, theU-profile rubber 17 pierced, and the rest of the first chamber 8 andpart of the second chamber 9 filled, with the nozzle 6 in the upperposition. After the injection needle has been removed, the piston unit7, consisting of inner piston body 18 with flange 22 and outer U-profilepiston ring 17, is advanced as far as the annular surface 16, such thatthe air 19 remaining in front of the nozzle 6 is then displaced as inFIG. 5. After it has been connected to the drive unit, the system isthen ready for storage or administration.

In the same way as is shown in FIG. 7, a multi-nozzle cylinder/pistonunit can be filled by hand, as shown in FIG. 8. The mechanical fillingis done analogously to the single-nozzle version.

FIG. 9 shows a bottom view of a version of the cylinder 3 with an endwall 5 and one nozzle 6.

FIG. 10 shows a bottom view of a version of the cylinder 3 with an endwall 5 and four nozzles 6.

LIST OF REFERENCE SIGNS

-   -   1 cylinder/piston unit    -   2 cylinder, blocking water vapor and oxygen    -   3 chamber    -   4 injection solution    -   5 end wall    -   6 nozzle bore or outlet element    -   7 piston, consisting of outer piston ring 17, inner piston body        18 and flange 22    -   8 first chamber    -   9 second chamber    -   10 closure piece    -   11 jacket surface    -   12 outside end wall    -   13 outer cylinder, pressure-stable    -   14 inside of chamber or of outflow funnel    -   15 outflow funnel    -   16 annular surface    -   17 outer piston ring, U-profile ring    -   18 inner piston body    -   19 gas bubble/air pocket    -   20 upper edge    -   21 piston rod    -   22 flange of the piston rod, also separate design    -   23 retainer element    -   24 spring hook    -   25 trigger, trigger tube    -   26 membrane on closure piece 10    -   27 membrane on cylinder, alternatively    -   28 trigger path    -   29 cone, truncated    -   30 profile ring    -   31 sealing lip of inner piston body 18    -   A, B, C annular pressure contours

What is claimed is:
 1. A method for filling a cylinder/piston unit (1)for a needle-free injector, the cylinder/piston unit (1) comprising achamber (3) arranged in a cylinder (2), the chamber (3) for long-termand sterile storage of an injection solution (4), an end wall (5) withat least one nozzle bore or one outlet element (6), a pressure-stableouter cylinder (13), and a pressure-stable piston (7) arranged movablyin the chamber (3) and blocking water vapor and oxygen, the chamber (3)formed with a first chamber (8) and a second, concentric chamber (9),wherein the cross section of the first chamber (8) is greater than thecross section of the second chamber (9), and each nozzle bore or eachoutlet element (6) is closed in a sterile manner by a membrane (26, 27)for blocking water vapor and oxygen and the membrane (26, 27) opens atan overpressure and the piston (7) comprising an inner piston body (18)and a flange (22), the piston (7) is surrounded by an outer compressiblepiston ring (17) for blocking water vapors and oxygen in a pressurestable and sterile closing manner, a transition area between the firstchamber (8) and the second chamber (9) is formed as an interior annularsurface (16) of cylinder (2), at least one of the cylinder (2) and outercylinder (13) including annular pressure contours (A), (B) and (C), saidmethod comprising at least the following steps: filling the secondchamber (9) with an injection solution (4), wherein the volume of theinjection solution (4) is smaller than the volume of the second chamber(9); inserting the piston (7) with a compressed outer piston ring (17),so that the air flow passes by, into the first chamber (8) until itbears on the annular surface (16) in order to close the second chamber(9), wherein a gas cushion remains in the second chamber (9); rotatingthe piston/cylinder unit through about 180 degrees about the horizontalaxis and waiting until the gas cushion in the second chamber (9) hasrisen fully upward to the at least the one nozzle bore or one outletelement (6); moving the inner piston body (18) with the flange (22) bymeans of the piston rod (21) out of the outer piston ring (17) into thesecond chamber (9), wherein the gas cushion is forced through the nozzlebore(s) or outlet element(s) (6) from the second chamber (9), and, themembrane (26) of a closure cap (10), or the separate membrane (27),lifts off from the nozzle bore(s) or outlet element(s) (6) and annularpressure contours A, B and C, and, after the emergence of the gascushion, again closes the nozzle bore(s) or outlet element(s) (6) at theannular pressure contours A, B and C in a sterile manner.
 2. The methodas claimed in claim 1, further comprising the of step of the completeemergence of the gas cushion is detected by the surveillance of thenozzle bore(s) or respectively the outlet element(s) (6) by a lightbarrier with respect to the release of the injection solution.
 3. Themethod as claimed in claim 1, said method further comprising the step ofa manual filling of a cylinder-piston unit (1) wherein the piston (7)being positioned about 2-3 millimetres in front of the annular surface(16); and, with the nozzle (6) pointing upward, the injection solution(4) is injected through the outer piston ring (17) into the chamber (3);and, by advancing the piston (7) up to the annular surface (16), andfurther advancing the inner piston body (18), the air is forced throughthe overpressure valve formed by the membrane (26) or the membrane (27).